Method for the production of pyrrolidine-1,2-dicarboxylic acid-1-(phenyl(-amide))-2-(phenyl(-amide)) derivatives and 1-(phenylcarbamoyl)-pyrrolidine-2-carboxylic acid derivatives as intermediate products

ABSTRACT

Process for the preparation of compounds of the formula I in which R, R 1 , R 2  and R 3  are as defined in Patent claim 1, and compounds of the formula IV in which R and R 1  are as defined in Patent claim 1, are intermediates for the preparation of the compounds of the formula I.

The invention relates to a process for the preparation of compounds ofthe formula I

in which

-   R is Hal or C≡CH,-   R¹ is H, ═O, Hal, A, OH, OA, A-COO—, A-CONH—, A-CONA-, N₃, NH₂, NO₂,    CN, COOH, COOA, CONHA, CONH₂, CON(A)₂, O-allyl, O-propargyl,    O-benzyl, ═N—OH or ═N-OA,-   R² is H, Hal or A,-   R³ is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,    2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,    2-oxo-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl,    2-iminopiperidin-1-yl, 2-imino-pyrrolidin-1-yl,    3-iminomorpholin-4-yl, 2-iminoimidazolidin-1-yl,    2-imino-1H-pyrazin-1-yl, 2,6-dioxopiperidin-1-yl,    2-oxopiperazin-1′-yl, 2,6-dioxopiperazin-1-yl,    2,5-dioxopyrrolidin-1-yl, 2-oxo-1,3-oxazolidin-3-yl,    3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl (=2-oxoazepan-1-yl),    2-azabicycle[2.2.2]octan-3-on-2-yl, 5,6-dihydro-1    H-pyrimidin-2-oxo-1-yl, 2-oxo-1,3-oxazinan-3-yl or    4H-1,4-oxazin-4-yl,    -   where the radicals may also be mono- or disubstituted by A or        OA,-   A is unbranched, branched or cyclic alkyl having 1-10 carbon atoms,    in which, in addition, 1-7H atoms may be replaced by F,-   Hal is F, Cl, Br or I,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, characterised in    that    a) a compound of the formula II    in which-   R¹ is as defined above,    is reacted with a compound of the formula III    in which-   R is as defined above,    to give a compound of the formula IV    in which-   R and R¹ are as defined above,    b) a compound of the formula IV is then reacted with a compound of    the formula V    in which R² and R³ are as defined above,    to give a compound of the formula I, and    c) this is, if desired, converted into pharmaceutically usable    derivatives and/or solvates thereof    by converting a base or acid of the formula I into one of its salts.

The invention had the object of finding novel improved processes for thepreparation of factor Xa inhibitors.

Compared with known processes from the prior art, the process accordingto the invention is shorter and more efficient.

Factor Xa inhibitors can be employed for combating and preventingthromboembolic diseases, such as thrombosis, myocardial infarction,arteriosclerosis, inflammation, apoplexia, angina pectoris, restenosisafter angioplasty and claudicatio intermittens.

Factor Xa is one of the proteases involved in the complex process ofblood coagulation. Factor Xa catalyses the conversion of prothrombininto thrombin. Thrombin cleaves fibrinogen into fibrin monomers, which,after crosslinking, make an elementary contribution to thrombusformation. Activation of thrombin may result in the occurrence ofthromboembolic diseases. However, inhibition of thrombin may inhibit thefibrin formation involved in thrombus formation.

The inhibition of thrombin can be measured, for example by the method ofG. F. Cousins et al. in Circulation 1996, 94, 1705-1712.

Inhibition of factor Xa can thus prevent the formation of thrombin.

The inhibition of factor Xa and the measurement of the anticoagulant andantithrombotic activity can be determined by conventional in-vitro orin-vivo methods. A suitable method is described, for example, by J.Hauptmann et al. in Thrombosis and Haemostasis 1990, 63, 220-223.

The inhibition of factor Xa can be measured, for example by the methodof T. Hara et al. in Thromb. Haemostas. 1994, 71, 314-319.

Coagulation factor VIIa initiates the extrinsic part of the coagulationcascade after binding to tissue factor and contributes to the activationof factor X to give factor Xa. Inhibition of factor VIla thus preventsthe formation of factor Xa and thus subsequent thrombin formation.

The inhibition of factor Vila and the measurement of the anticoagulantand antithrombotic activity can be determined by conventional in-vitroor in-vivo methods. A conventional method for the measurement of theinhibition of factor VIIa is described, for example, by H. F. Ronning etal. in Thrombosis Research 1996, 84, 73-81.

Coagulation factor IXa is generated in the intrinsic coagulation cascadeand is likewise involved in the activation of factor X to give factorXa. Inhibition of factor IXa can therefore prevent the formation offactor Xa in a different way.

The inhibition of factor IXa and the measurement of the anticoagulantand antithrombotic activity can be determined by conventional in-vitroor in-vivo methods. A suitable method is described, for example, by J.Chang et al. in Journal of Biological Chemistry 1998, 273, 12089-12094.

A correlation between tissue factor TF/factor VIIa and the developmentof various types of cancer has been indicated by T. Taniguchi and N. R.Lemoine in Biomed. Health Res. (2000), 41 (Molecular Pathogenesis ofPancreatic Cancer), 57-59. The publications listed below describe anantitumoural action of TF-VII and factor Xa inhibitors for various typesof tumour:

-   K. M. Donnelly et al. in Thromb. Haemost. 1998; 79: 1041-1047;-   E. G. Fischer et al. in J. Clin. Invest. 104: 1213-1221 (1999);-   B. M. Mueller et al. in J. Clin. Invest. 101: 1372-1378 (1998);-   M. E. Bromberg et al. in Thromb. Haemost. 1999; 82: 88-92.

WO 03/045912 describes a route which is longer by 2 steps, whichproceeds via an N-protected pyrrolidine derivative, for example BOC-Pro:

Helv. Chim. Acta 1998, 81, 1254-1263 describes the reaction of primaryamines with 4-chlorophenyl isocyanate (route A]).

As shown in route B], the reactive side-chain groups, such as OH, NH orSH, also react therein to give bisaddition products.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds and so-called prodrug compounds.

Above and below, A denotes alkyl, is unbranched (linear) or branched,and has 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms. A preferablydenotes methyl, furthermore ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl or tert-butyl, furthermore also pentyl, 1-, 2- or3-methylbutyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl,1-, 2-, 3- or 4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or3,3-dimethylbutyl, 1- or 2-ethylbutyl, 1-ethyl-1-methyl-propyl,1-ethyl-2-methylpropyl, 1,1,2- or 1,2,2-trimethylpropyl, furthermorepreferably, for example, trifluoromethyl.

A is very particularly preferably alkyl having 1, 2, 3, 4, 5 or 6 carbonatoms, preferably methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, hexyl or trifluoromethyl.

Hal is preferably F, Cl or Br, but also I.

The invention preferably relates to a process according to claim 1 forthe preparation of compounds of the formula I in which R is F or Cl.

Preference is furthermore given to a process according to claim 1 or 2for the preparation of compounds of the formula I in which

-   R¹ is H, ═O, OH, OA, A-COO—, N₃, NH₂, O-allyl or O-propargyl.

Particular preference is given to a process according to claim 1 or 2for the preparation of compounds of the formula I in which R¹ is H orOH.

Preference is furthermore given to a process according to claims 1-4 forthe preparation of compounds of the formula I in which

-   R³ is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,    2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,    2-oxo-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2-oxopiperazin-1-yl    or 3-oxo-2H-pyridazin-2-yl.

Preference is furthermore given to a process according to claims 1-5 forthe preparation of compounds of the formula I in which

A is unbranched or branched alkyl having 1-6 carbon atoms, in which, inaddition, 1-3H atoms may be replaced by F.

Preference is furthermore given to a process according to one or more ofclaims 1-6 for the preparation of compounds of the formula I in which Ris Hal or C≡CH,

-   R¹ is H, OH or OA,-   R² is H, Hal or A,-   R³ is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,    2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,    2-oxo-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2-oxopiperazin-1-yl    or 3-oxo-2H-pyridazin-2-yl,-   A is unbranched, branched or cyclic alkyl having 1-10 carbon atoms,    in which, in addition, 1-7H atoms may be replaced by F,-   Hal is F, Cl, Br or I,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

Preference is furthermore given to a process according to one or more ofclaims 1-7 for the preparation of compounds of the formula I in which

-   R is For Cl,-   R¹ is H, ═O, OH, OA, A-COO—, N₃, NH₂, O-allyl or O-propargyl,-   R² is H, For A,-   R³ is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,    2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,    2-oxo-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2-oxopiperazin-1-yl    or 3-oxo-2H-pyridazin-2-yl,-   A is unbranched or branched alkyl having 1-6 carbon atoms, in which,    in addition, 1-3H atoms may be replaced by F,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

Particular preference is given to a process according to one or more ofclaims 1-8 for the preparation of compounds of the formula I in which

-   R is For C¹,-   R¹ is H or OH,-   R² is H, For A,-   R³ is 3-oxomorpholin-4-yl,-   A is unbranched or branched alkyl having 1-6 carbon atoms, in which,    in addition, 1-3H atoms may be replaced by F,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

Very particular preference is given to a process according to one ormore of claims 1-15 for the preparation of compounds of the formula Ia

in which

-   R is F or Cl,-   R¹ is H or OH,-   R² is H, F or A,-   R³ is 3-oxomorpholin-4-yl,-   A is unbranched or branched alkyl having 1-6 carbon atoms, in which,    in addition, 1-3H atoms may be replaced by F,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios, characterised in    that    a) a compound of the formula II    in which-   R¹ is H or OH,    is reacted with a compound of the formula III    in which-   R is F or Cl,    in aqueous alkali metal or alkaline earth metal carbonate or    bicarbonate solution, at a temperature between 60° and 110° C.,    to give a compound of the formula IV    in which-   R is F or C¹,-   R¹ is H or OH,    b) a compound of the formula IV is then reacted with a compound of    the formula V    in which-   R² is H, F or A,-   R³ is 3-oxomorpholin-4-yl,-   A is unbranched or branched alkyl having 1-6 carbon atoms, in which,    in addition, 1-3H atoms may be replaced by F,    in the presence of an auxiliary reagent with formation of a mixed    anhydride, at a temperature between 10° and 70° C.,    to give a compound of the formula Ia, and    c) this is, if desired, converted into pharmaceutically usable    derivatives and/or solvates thereof    by converting a base or acid of the formula Ia into one of its    salts.

The compounds of the formula I or Ia can preferably be obtained byreacting compounds of the formula II with compounds of the formula IIIin a first step a).

The reaction is generally carried out in an inert solvent, in thepresence of an acid-binding agent, preferably an alkali metal oralkaline earth metal hydroxide, carbonate or bicarbonate or another saltof a weak acid of the alkali or alkaline earth metals, preferably ofpotassium, sodium, calcium or caesium, such as, for example, NaOH,sodium carbonate, potassium carbonate, caesium carbonate or NaHCO₃.

Particular preference is given to NaHCO₃.

It may also be favourable to add an organic base, such as triethylamine,dimethylaniline, pyridine or quinoline. The reaction time is between afew minutes and 14 days, preferably between one and ten hours, dependingon the conditions used, and the reaction temperature is between about 0°and 150°, normally between 20° and 130°, preferably between 60° and110°, very particularly preferably between 70° and 90° C.

Examples of suitable inert solvents are water; hydrocarbons, such ashexane, petroleum ether, benzene, toluene or xylene; chlorinatedhydrocarbons, such as trichloroethylene, 1,2-dichloroethane,tetrachloromethane, chloroform or dichloromethane; alcohols, such asmethanol, ethanol, isopropanol, n-propanol, n-butanol or tert-butanol;ethers, such as diethyl ether, diisopropyl ether, tetrahydrofuran (THF)or dioxane; glycol ethers, such as ethylene glycol monomethyl ormonoethyl ether or ethylene glycol dimethyl ether (diglyme); ketones,such as acetone, isobutyl methyl ketone (IBMK) or butanone; amides, suchas acetamide, dimethylacetamide or dimethylformamide (DMF); nitriles,such as acetonitrile; sulfoxides, such as dimethyl sulfoxide (DMSO);carbon disulfide; carboxylic acids, such as formic acid or acetic acid;nitro compounds, such as nitromethane or nitrobenzene; esters, such asethyl acetate, or mixtures of the said solvents.

Particular preference is given to water.

In a second step, compounds of the formula IV are reacted with compoundsof the formula V.

The reaction is preferably carried out in the presence of an auxiliaryreagent which forms an intermediate derivative with the OH group of thecarboxylic acid, such as, for example, a mixed anhydride, an activatedester, an imidazolide or is converted into an alkylsulfonyloxy grouphaving 1-6 carbon atoms (preferably methylsulfonyloxy ortrifluoromethylsulfonyloxy) or arylsulfonyloxy having 6-10 carbon atoms(preferably phenyl- or p-tolylsulfonyloxy).

Radicals of this type for activation of the carboxyl group in typicalacylation reactions are described in the literature (for example in thestandard works, such as Houben-Weyl, Methoden der organischen Chemie[Methods of Organic Chemistry], Georg-Thieme-Verlag, Stuttgart).

The coupling can be carried out using various condensation reagents,such as carbodiimides, carbodiimidazole, those of the uronium type, suchas TBTU, and acid halide or activated ester methods. Activated estersare advantageously formed in situ, for example by addition of HOBt orN-hydroxysuccinimide.

Preference is given to the formation of a mixed anhydride.

Particular preference is given here to the use of ethyl2-ethoxy-1,2-dihydroquinoline-1-carboxylate (EEDQ).

The reaction is generally carried out in an inert solvent.

The reaction time is between a few minutes and 14 days, preferablybetween one and twenty hours, depending on the conditions used, and thereaction temperature is between about 0° and 150°, normally between 0°and 90°, preferably between 10° and 70°, particularly preferably between15° and 30° C.

Examples of suitable inert solvents are hydrocarbons, such as hexane,petroleum ether, benzene, toluene or xylene; chlorinated hydrocarbons,such as trichloroethylene, 1,2-dichloroethane, tetrachloromethane,chloroform or dichloromethane; alcohols, such as methanol, ethanol,iso-propanol, n-propanol, n-butanol or tert-butanol; ethers, such asdiethyl ether, diisopropyl ether, tetrahydrofuran (THF) or dioxane;glycol ethers, such as ethylene glycol monomethyl or monoethyl ether orethylene glycol dimethyl ether (diglyme); ketones, such as acetone orbutanone; amides, such as acetamide, dimethylacetamide ordimethylformamide (DMF); nitriles, such as acetonitrile; sulfoxides,such as dimethyl sulfoxide (DMSO); carbon disulfide; carboxylic acids,such as formic acid or acetic acid; nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents, particularly preferably tetra hydrofuran.

A base of the formula I, Ia or of the formula IV can be converted intothe associated acid-addition salt using an acid, for example by reactionof equivalent amounts of the base and the acid in an inert solvent, suchas ethanol, followed by evaporation. Suitable acids for this reactionare, in particular, those which give physiologically acceptable salts.Thus, it is possible to use inorganic acids, for example sulfuric acid,nitric acid, hydrohalic acids, such as hydrochloric acid or hydrobromicacid, phosphoric acids, such as orthophosphoric acid, or sulfamic acid,furthermore organic acids, in particular aliphatic, alicyclic,araliphatic, aromatic or heterocyclic monobasic or polybasic carboxylic,sulfonic or sulfuric acids, for example formic acid, acetic acid,propionic acid, pivalic acid, diethyl-acetic acid, malonic acid,succinic acid, pimelic acid, fumaric acid, maleic acid, lactic acid,tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid,nicotinic acid, isonicotinic acid, methane- or ethanesulfonic acid,ethanedisulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid, naphthalenemono- and -disulfonic acids, orlaurylsulfuric acid. Salts with physiologically unacceptable acids, forexample picrates, can be used for the isolation and/or purification ofthe compounds of the formula I.

On the other hand, compounds of the formula I, Ia or IV can be convertedinto the corresponding metal salts, in particular alkali metal oralkaline earth metal salts, or into the corresponding ammonium saltsusing bases (for example sodium hydroxide, potassium hydroxide, sodiumcarbonate or potassium carbonate).

It is also possible to use physiologically acceptable organic bases,such as, for example, ethanolamine.

The invention furthermore relates to compounds of the formula IV

in which

-   R is Hal or C—CH,-   R¹ is H, ═O, Hal, A, OH, OA, A-COO—, A-CONH—, A-CONA-, N₃, NH₂, NO₂,    CN, COOH, COOA, CONH₂, CONHA, CON(A)₂, O-allyl, O-propargyl,    O-benzyl, ═N—OH or ═N-OA,-   A is unbranched, branched or cyclic alkyl having 1-10 carbon atoms,    in which, in addition, 1-7H atoms may be replaced by F,-   Hal is F, Cl, Br or I,    and pharmaceutically usable derivatives, solvates and stereoisomers    thereof, including mixtures thereof in all ratios.

The invention also relates to the optically active forms(stereoisomers), the enantiomers, the racemates, the diastereomers andthe hydrates and solvates of the compounds according to the invention.

The term solvates of the compounds is taken to mean adducts of inertsolvent molecules onto the compounds which form owing to their mutualattractive force. Solvates are, for example, mono- or dihydrates oralcoholates.

The term pharmaceutically usable derivatives is taken to mean, forexample, the salts of the compounds according to the invention andso-called prodrug compounds.

The term prodrug derivatives is taken to mean compounds of the formula Iwhich have been modified by, for example, alkyl or acyl groups, sugarsor oligopeptides and which are rapidly cleaved in the organism to givethe effective compounds according to the invention.

These also include biodegradable polymer derivatives of the compoundsaccording to the invention, as described, for example, in Int. J. Pharm.115, 61-67 (1995).

The invention also relates to mixtures of the compounds of the formulaIV according to the invention, for example mixtures of twodiastereomers, for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10,1:100 or 1:1000.

These are particularly preferably mixtures of stereoisomeric compounds.

In particular, the compounds of the formula IV can be used in processesfor the preparation of compounds of the formula I.

Other ethynyl derivatives are described in WO 02/079145 as factor Xainhibitors.

Other aromatic amides are described in WO 99/00121 and in WO 00/39118.Aromatic amidine derivatives having an antithrombotic action aredisclosed, for example, in EP 0 540 051 B1. Cyclic guanidines for thetreatment of thromboembolic diseases are described, for example, in WO97/08165. Aromatic heterocyclic compounds having a factor Xa-inhibitoryactivity are disclosed, for example, in WO 96/10022. SubstitutedN-[(aminoiminomethyl)phenylalkyl]azaheterocyclylamides as factor Xainhibitors are described in WO 96/40679.

For all radicals which occur more than once, their meanings areindependent of one another.

A denotes alkyl, is unbranched (linear) or branched and has 1, 2, 3, 4,5, 6, 7, 8, 9 or 10 carbon atoms. A preferably denotes methyl,furthermore ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl ortert-butyl, furthermore also pentyl, 1-, 2- or 3-methylbutyl, 1,1-, 1,2-or 2,2-dimethylpropyl, 1-ethylpropyl, hexyl, 1-, 2-, 3- or4-methylpentyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1- or2-ethylbutyl, 1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, furthermore preferably, for example,trifluoromethyl.

A very particularly preferably denotes alkyl having 1, 2, 3, 4, 5 or 6carbon atoms, preferably methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl, tert-butyl, pentyl, hexyl or trifluoromethyl.

Hal preferably denotes F, Cl or Br, but also 1.

R preferably denotes F or Cl.

R¹ preferably denotes H, ═O, OH, OA, A-COO—, N₃, NH₂, O-allyl orO-propargyl, particularly preferably H or OH.

Particular preference is given to compounds of the formula IV selectedfrom the group consisting of

-   (2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylic    acid,-   (2R)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid.

Compounds of the formula IV according to the invention may be chiralowing to their molecular structure and may accordingly occur in variousenantiomeric forms. They may therefore be in racemic or optically activeform.

Since the pharmaceutical efficacy of the racemates or stereoisomers ofthe end products resulting from the intermediate compounds may bedifferent, it may be desirable to use the enantiomers of the compoundsaccording to the invention. In these cases, the end product or even theintermediates can be separated into enantiomeric compounds by chemicalor physical measures known to the person skilled in the art or alreadyemployed as such in the synthesis.

In the case of racemic amines, diastereomers are formed from the mixtureby reaction with an optically active resolving agent. Suitable resolvingagents are, for example, optically active acids, such as the R and Sforms of tartaric acid, diacetyltartaric acid, dibenzoyltartaric acid,mandelic acid, malic acid, lactic acid, suitably N-protected amino acids(for example N-benzoylproline or N-benzenesulfonylproline) or thevarious optically active camphorsulfonic acids. Also advantageous ischromatographic resolution of the enantiomers with the aid of anoptically active resolving agent (for exampledinitrobenzoylphenylglycine, cellulose triacetate or other derivativesof carbohydrates or chirally derivatised methacrylate polymersimmobilised on silica gel). Suitable eluents for this purpose areaqueous or alcoholic solvent mixtures, such as, for example,hexane/iso-propanol/acetonitrile, for example in the ratio 82:15:3.

Above and below, all temperatures are indicated in ° C. In the followingexamples, “conventional work-up” means that water is added if necessary,the pH is adjusted, if necessary, depending on the constitution of theend product, to values between 2 and 10, the mixture is extracted withethyl acetate or dichloromethane, the phases are separated, the organicphase is dried over sodium sulfate and evaporated, and the product ispurified by chromatography on silica gel and/or by crystallisation. Rfvalues on silica gel; eluent: ethyl acetate/methanol 9:1.

Mass spectrometry (MS): EI (electron impact ionisation) M⁺; ESI(electro-spray ionisation) (M+H)⁺; FAB (fast atom bombardment) (M+H)⁺.

EXAMPLE 1

1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)-phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamideis prepared analogously to the following scheme:

1.1 13.1 g (0.1 mol) of cis-hydroxy-D-proline are dissolved in 800 ml ofNaHCO₃ solution (c=0.5 mol/l), 30.7 g (0.2 mol) of 4-chlorophenyliso-cyanate are subsequently added, and the mixture is stirred at 80° C.for hours. The reaction mixture is cooled to RT, the precipitatedsymmetrical urea 1,3-bis(4-chlorophenyl)urethane is filtered off withsuction and washed with water, and the aqueous phase is adjusted to pH=1using about 40 ml of conc. HCl. The precipitated product is separatedoff, the aqueous phase is post-extracted with EA, and both organic partsare dried. The residue is then recrystallised from MTB ether, giving23.3 g (81.8%) of(2R,4R)-1-(4-chlorophenylcarbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid 3; m.p. 132-134°; MS (FAB): m/e=285 (M+H⁺).

¹H NMR (DMSO-d₆) δ 12.00 (sbr, 1H), 8.39 (s, 1H), 7.54 (d, J=8.9 Hz,2H), 7.26 (d, J=8.9 Hz, 2H), 4.41-4.24 (m, 2H), 3.66 (dd, J=5.7 and 5.8Hz, 1H), 3.33 (dd, J=4.0 and 4.1 Hz, 1H), 2.40-2.25 (m, 1H), 1.96-1.81(m, 1H).

Optical rotation: [α]²⁰ _(D)=+43.7°; MeOH, c=0.0198 g/2 ml

C,H,N: Theoretical C, 50.63; H, 4.60; N, 9.84 Found C, 51.1; H, 4.6; N,9.0.

1.2 14.24 g (0.05 mol) of 3, 9.61 g (0.05 mol) ofaminophenyl-morpholinone 4 and 12.37 g (0.05 mol) of ethyl2-ethoxy-1,2-dihydroquinoline-1-carboxylate are dissolved in 400 ml oftetrahydrofuran at RT and stirred for 20 hours, during which asuspension forms. The precipitate is filtered off with suction, rinsedthree times with THF and evaporated to dryness under reduced pressure,giving 15.9 g (69%) of1-[(4-chlorophenyl)]-2-{[4-(3-oxo-morpholin-4-yl)-phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide5; m.p. 208-210°; MS (FAB): m/e=459 (M+H⁺).

The following is obtained analogously to Example 1.1:(2R)-1-(4-chlorophenylcarbamoyl)pyrrolidine-2-carboxylic acid, m.p.173-175°,

MS (FAB): m/e=269 (M+H⁺);

¹H NMR (DMSO-d₆) δ 12.37 (sbr, 1H), 8.37 (s, 1H), 7.53 (d, J=8.9 Hz,2H), 7.26 (d, J=8.9 Hz, 2H), 4.32 (dd, J=3.5 Hz, 1H), 3.60-3.41 (m, 2H),2.27-2.07 (m, 1H), 2.00-1.81 (m, 3H).

Optical rotation: [α]²⁰ _(D)=+60.9°; MeOH, c=0.0189 g/2 ml

C,H,N: Theoretical C, 53.64; H, 4.88; N, 10.43 Found C, 53.6; H, 5.1; N,10.4.

EXAMPLE 2

The following compounds are obtained analogously to Example 1:

-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[3-trifluoromethyl-4-(3-oxomorpholin-4-yl)-phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-azidopyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorphoiin-4-yl)phenyl]}-(2R,4S)-4-aminopyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-acetoxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-4-oxopyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2S)-pyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-allyloxypyrrolidine-1,2-dicarboxamide,-   1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-(prop-2-ynyloxy)pyrrolidine-1,2-dicarboxamide.

EXAMPLE 3

The reaction of L-hydroxyproline with 4-chlorophenyl isocyanate can becarried out analogously to Example 1.1, preferably also with oneequivalent of chlorophenyl isocyanate, preferably in isobutyl methylketone (IBMK).

9.4 g (71.685 mmol) of L-hydroxyproline are dissolved in 71.68 ml ofNaOH solution (c=1 mol/l) at from −2 to 0° C., a solution of 11.008 g(71.685 mmol) of 4-chlorophenyl isocyanate in 70 ml of IBMK issubsequently added, and the mixture is stirred at −1° C. for 1 hour.Conventional work-up gives 18.52 g of(2S,4R)-1-(4-chlorophenyl-carbamoyl)-4-hydroxypyrrolidine-2-carboxylicacid;

Yield: 91%.

1. Process for the preparation of compounds of the formula I

in which R is Hal or C≡CH, R¹ is H, ═O, Hal, A, OH, OA, A-COO—, A-CONH—,A-CONA-, N₃, NH₂, NO₂, CN, COOH, COOA, CONH₂, CONHA, CON(A)₂, O-allyl,O-propargyl, O-benzyl, ═N—OH or ═N-OA, R² is H, Hal or A, R³ is2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl,3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2-oxo-1H-pyrazin-1-yl,2-oxoimidazolidin-1-yl, 2-iminopiperidin-1-yl, 2-iminopyrrolidin-1-yl,3-iminomorpholin-4-yl, 2-iminoimidazolidin-1-yl,2-imino-1H-pyrazin-1-yl, 2,6-dioxopiperidin-1-yl, 2-oxopiperazin-1-yl,2,6-dioxopiperazin-1-yl, 2,5-dioxopyrrolidin-1-yl,2-oxo-1,3-oxazolidin-3-yl, 3-oxo-2H-pyridazin-2-yl, 2-caprolactam-1-yl(=2-oxoazepan-1-yl), 2-azabicyclo[2.2.2]octan-3-on-2-yl,5,6-dihydro-1H-pyrimidin-2-oxo-1-yl, 2-oxo-1,3-oxazinan-3-yl or4H-1,4-oxazin-4-yl, where the radicals may also be mono- ordisubstituted by A or OA, A is unbranched, branched or cyclic alkylhaving 1-10 carbon atoms, in which, in addition, 1-7H atoms may bereplaced by F, Hal is F, Cl, Br or I, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios, characterised in that a) a compound of theformula II

in which R¹ is as defined above, is reacted with a compound of theformula III

in which R is as defined above, to give a compound of the formula IV

in which R and R¹ are as defined above, b) a compound of the formula IVis then reacted with a compound of the formula V

in which R² and R³ are as defined above, to give a compound of theformula I, and c) this is, if desired, converted into pharmaceuticallyusable derivatives and/or solvates thereof by converting a base or acidof the formula I into one of its salts.
 2. Process according to claim 1for the preparation of compounds of the formula I in which R is For Cl,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 3. Process accordingto claim 1 for the preparation of compounds of the formula I in which R¹is H, ═O, OH, OA, A-COO—, N₃, NH₂, O-allyl or O-propargyl, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 4. Process according to claim1 for the preparation of compounds of the formula I in which R¹ is H orOH, and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 5. Process accordingto claim 1 for the preparation of compounds of the formula I in which R³is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl,3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl, 2-oxo-1H-pyrazin-1-yl,2-oxoimidazolidin-1-yl, 2-oxopiperazin-1-yl or 3-oxo-2H-pyridazin-2-yl,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 6. Process accordingto claim 1 for the preparation of compounds of the formula I in which Ais unbranched or branched alkyl having 1-6 carbon atoms, in which, inaddition, 1-3H atoms may be replaced by F, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 7. Process according to claim 1 for thepreparation of compounds of the formula I in which R is Hal or C≡CH, R¹is H, OH or OA, R² is H, Hal or A, R³ is 2-oxopiperidin-1-yl,2-oxopyrrolidin-1-yl, 2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl,4-oxo-1H-pyridin-1-yl, 2-oxo-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl,2-oxopiperazin-1-yl or 3-oxo-2H-pyridazin-2-yl, A is unbranched,branched or cyclic alkyl having 1-10 carbon atoms, in which, inaddition, 1-7H atoms may be replaced by F, Hal is F, Cl, Br or I, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios.
 8. Process according to claim1 for the preparation of compounds of the formula I in which R is F orCl, R¹ is H, ═O, OH, OA, A-COO—, N₃, NH₂, O-allyl or O-propargyl, R² isH, F or A, R³ is 2-oxopiperidin-1-yl, 2-oxopyrrolidin-1-yl,2-oxo-1H-pyridin-1-yl, 3-oxomorpholin-4-yl, 4-oxo-1H-pyridin-1-yl,2-oxo-1H-pyrazin-1-yl, 2-oxoimidazolidin-1-yl, 2-oxopiperazin-1-yl or3-oxo-2H-pyridazin-2-yl, A is unbranched or branched alkyl having 1-6carbon atoms, in which, in addition, 1-3H atoms may be replaced by F,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 9. Process accordingto claim 1 for the preparation of compounds of the formula I in which Ris F or Cl, R¹ is H or OH, R² is H, F or A, R³ is 3-oxomorpholin-4-yl, Ais unbranched or branched alkyl having 1-6 carbon atoms, in which, inaddition, 1-3H atoms may be replaced by F, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 10. Process according to claim 1, in which thereaction in step a) is carried out in an inert solvent or solventmixture, in the presence of an alkali or alkaline earth metal hydroxide,carbonate or bicarbonate.
 11. Process according to claim 1, in which thereaction in step a) is carried out in aqueous NaHCO₃ solution. 12.Process according to claim 1, in which the reaction in step a) iscarried out at a temperature between 60° and 110° C.
 13. Processaccording to claim 1, in which the reaction in step b) is carried out inthe presence of ethyl 2-ethoxy-1,2-dihydroquinoline-1-carboxylate(EEDQ).
 14. Process according to claim 1, in which the reaction in stepb) is carried out at a temperature between 10° and 70° C.
 15. Processaccording to claim 1, in which the reaction in step b) is carried out intetrahydrofuran.
 16. Process according to claim 1 for the preparation ofcompounds of the formula Ia

in which R is For Cl, R¹ is H or OH, R² is H, F or A, R³ is3-oxomorpholin-4-yl, A is unbranched or branched alkyl having 1-6 carbonatoms, in which, in addition, 1-3H atoms may be replaced by F, andpharmaceutically usable derivatives, solvates and stereoisomers thereof,including mixtures thereof in all ratios, characterised in that a) acompound of the formula II

in which R¹ is H or OH, is reacted with a compound of the formula III

in which R is F or Cl, in aqueous alkali metal or alkaline earth metalcarbonate or bicarbonate solution, at a temperature between 60° and 110°C., to give a compound of the formula IV

in which R is For Cl, R¹ is H or OH, b) a compound of the formula IV isthen reacted with a compound of the formula V

in which R² is H, F or A, R³ is 3-oxomorpholin-4-yl, A is unbranched orbranched alkyl having 1-6 carbon atoms, in which, in addition, 1-3Hatoms may be replaced by F, in the presence of an auxiliary reagent withformation of a mixed anhydride, at a temperature between 10° and 70° C.,to give a compound of the formula Ia, and c) this is, if desired,converted into pharmaceutically usable derivatives and/or solvatesthereof by converting a base or acid of the formula Ia into one of itssalts.
 17. Process according to claim 1 for the preparation of compoundsselected from the group consisting of1-[(4-chlor-phenyl)]-2-{[4-(3-oxo-morpholin-4-yl)-phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl])}-(2R)-pyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl])}-(2S,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[3-trifluoromethyl-4-(3-oxomorpholin-4-yl)-phenyl]}-(2R)-pyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[2-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-azidopyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4S)-4-aminopyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-methoxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-acetoxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R)-4-oxopyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[3-methyl-4-(3-oxomorpholin-4-yl)phenyl]}-(2S)-pyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[3-fluoro-4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-hydroxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2S,4S)-4-hydroxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-allyloxypyrrolidine-1,2-dicarboxamide,1-[(4-chlorophenyl)]-2-{[4-(3-oxomorpholin-4-yl)phenyl]}-(2R,4R)-4-(prop-2-ynyloxy)pyrrolidine-1,2-dicarboxamide.and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.
 18. Compounds of theformula IV

in which R is Hal or C≡CH, R¹ is H, ═O, Hal, A, OH, OA, A-COO—, A-CONH—,A-CONA-, N₃, NH₂, NO₂, CN, COOH, COOA, CONHA, CONH₂, CON(A)₂, O-allyl,O-propargyl, O-benzyl, ═N—OH or ═N-OA, A is unbranched, branched orcyclic alkyl having 1-10 carbon atoms, in which, in addition, 1-7H atomsmay be replaced by F, Hal is F, Cl, Br or I, and pharmaceutically usablederivatives, solvates and stereoisomers thereof, including mixturesthereof in all ratios.
 19. Compounds according to claim 18, in which Ris F or Cl, R¹ is H, ═O, OH, OA, A-COO—, N₃, NH₂, O-allyl orO-propargyl, and pharmaceutically usable derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios. 20.Compounds according to claim 18, in which R is F or Cl, R¹ is H or OH,and pharmaceutically usable derivatives, solvates and stereoisomersthereof, including mixtures thereof in all ratios.